Virus caused respiratory illnesses account for much of the suffering and inconvenience endured by mankind and animals generally, and, in some instances, account for high rates of mortality.
Influenza is one of the common diseases of man, infecting large segments of the population each year, typically during the fall and winter and early spring of the year, with great economic consequences and, occasionally, with great public health consequences. For example, more people died in the influenza epidemic of 1918 than died in World War I. Certain members of the family orthomyxoviridae infect humans, animals and birds, while certain other members infect only humans. Orthomyxoviridae, or flu virus, is an enveloped RNA virus consisting basically of an internal nucelocapsid and an envelope made up of a matrix protein, a lipid bilayer, and externalglycoproteins.
Notwithstanding that influenza has been extensively studied, very little progress has been made toward the prevention or cure of the disease. One reason for the slow progress toward preventing or treating influenza is the antigenic shift which presents frequent and often abrupt appearances of new serotypes with the consequence that an inactivated virus vaccine against one serotype may have little or no immunizing effect against other serotypes. It has, thus far, impossible to develop a single vaccine against all influenza based on antigenic determinants.
Influenza A and B viruses exhibit frequent minor antigenic drift and type A viruses undergo a major antigenic shift every one to four decades, thus assuring that at least a portion of the population is always susceptible. Children and young adults have the highest incidence of influenza infection each winter, but the highest incidences of severe or complicated influenza illness leading to hospitalization or death are in infants, elderly persons (especially those in nursing homes), and persons of all ages with underlying heart or lung disease. Influenza viruses infect respiratory epithelial cells and can themselves cause diffuse pulmonary infiltrates and severe hypoxia, but concomitant or secondary bacterial pneumonia is a much more frequent complication of influenza. (Influenza pneumonia, Ruben FL; Cate TR, Semin Respir Infect Jun 1987, 2 (2) p122-9.)
Members of the family paramyxoviridae are responsive for a number of serious diseases in humans and animals. Bronchiolitis is one of the most serious pulmonary infections commonly caused by respiratory syncytial virus (RSV), a member of the paramyxoviridae. RSV disease occurs in yearly epidemics and is most severe in children 1 year of age or younger. Approximately 1 in 50 to 1 in 100 infants are hospitalized after their first infection, and mortality fluctuates between 0.5 and 5.0 per cent. Patients with underlying conditions such as congenital heart disease and bronchopulmonary dysplasia are at higher risk for morbidity and mortality. Respiratory syncytial virus disease has also been documented in immunocompromised adults, aged 21 to 50, wherein the immune system had been comprised by bone marrow transplants, renal transplants, pancreas transplants and by T-cell lymphoma, based on specimens from bronchoalveolar lavage, sputum, throat, sinus aspirate, and lung biopsy. (Respiratory syncytial virus infection in immunocompromised adults, Englund JA; Sullivan CJ; Jordan MC; Dehner LP; Vercellotti GM; Balfour HH Jr, Ann Intern Med Aug 1 1988, 109 ( 3) p203-8.)
Pneumonias in adults due to mycoplasma, chlamydiae, and viruses are a common clinical problem. These microorganisms contribute to the etiologies in 6-35% of all cases of pneumonia and are the sole pathogens in 1-17% of hospitalized cases. Important trends and developments in the field include the emergence of a Chlamydia psittaci strain (TWAR) that is passaged from human to human, causes a mycoplasma-like illness, and that is relatively resistant to erythromycin, and the recognition of respiratory syncytial virus as a pathogen in nursing home outbreaks and in immunosuppressed adults, the continuing high lethality of fully developed influenza pneumonia, the efficacy of acyclovir and adenine arabinoside in limiting the complications of varicella-zoster virus infections, and the increasing frequency of pneumonia caused by cytomegalovirus and the severity of this disorder in highly immunosuppressed patients. Developments in the rapid diagnosis and therapy of respiratory syncytial virus infections with an aerosolized antiviral drug in children may pave the way for comparable advances in difficult pneumonias in adult patients. (Pneumonias in adults due to mycoplasma, chlamydiae, and viruses, Luby JP, Am J Med Sci Jul 1987, 294 (1) p45-64.)
Cytomegalovirus (CMV) pneumonia causes significant morbidity and mortality in bone marrow transplant recipients and in patients with AIDS. 9-(1,3-Dihydroxy-2-propoxymethyl) guanine (ganciclovir) and phosphonoformic acid (PFA) demonstrate activity against CMV in human infections, although recurrent CMV and systemic drug toxicity frequently develop. The efficacy of aerosol administration of antiviral agents against murine CMV (MCMV) infection has been examined using aerosolized ganciclovir, PFA, or ribavirin. The results suggest that aerosol administration of antiviral agents can potently and selectively inhibit replication of MCMV in the lung. (Aerosol administration of antiviral agents to treat lung infection due to murine cytomegalovirus. Debs RJ; Montgomery AB; Brunette EN; DeBruin M; Shanley JD, J Infect Dis (UNITED STATES) Feb 1988, 157 (2) p327-31.)
Broad spectrum anti-viral agents have only recently appeared and have not yet been established as generally efficacious, but have shown great promise in a few areas. (Antiviral agents, Hermans PE; Cockerill FR 3d, Mayo Clin Proc Dec 1987, 62 (12) p1108-15.) Progress is, however, being made in the development of drugs for the prevention and treatment of viral respiratory infections. Two drugs currently available to clinicians are amantadine (Symmetral) and ribavirin (Virazole). Oral amantadine is effective for both treatment and prevention of uncomplicated influenza A infections. Although vaccination continues as the mainstay of influenza prevention, amantadine is useful for unvaccinated patients if complications are likely. Ribavirin appears to be safe for treatment of respiratory syncytial virus infections in nonintubated infants. It must, however, be delivered by aerosol in a hospital setting. Another drug, rimantadine is similar to amantadine in its action and indications for use and has a lower incidence of side effects. (Antiviral drugs for common respiratory diseases. What's here, what's to come, Johnson DC, Postgrad Med Feb 1 1988, 83 (2) p136-9, 142-3, 146-8; Postgrad Med 1988 Apr;83(5):52.)
Aerosol or nebulizer inhalation therapy has been established as effective in treating, and possibly in preventing, certain virus induced diseases. Aerosol treatment using ribavirin was shown to alleviate the symptoms of influenza and to reduce the shedding of influenza virus from the respiratory tract, (Ribavirin aerosol treatment of influenza, Knight V; Gilbert BE, Infect Dis Clin North Am (UNITED STATES) Jun 1987, 1 (2) p441-57.) and with amantadine. (Favorable outcome after treatment with amantadine and ribavirin in a pregnancy complicated by influenza pneumonia. A case report. Kirshon B; Faro S; Zurawin RK; Samo TC; Carpenter RJ, J Reprod Med Apr 1988, 33 (4) p399-401.) Ribavirin aerosol is now used with some success in the treatment of RSV infections. (Ribavirin aerosol treatment of serious respiratory syncytial virus infection in infants, Rodriguez WJ; Parrott RH, Infect Dis Clin North Am (UNITED STATES) Jun 1987, 1 (2) p425-39.)
While some progress is being made in the field of inhalation therapy of virus caused infectious diseases, it is apparent from the foregoing discussion there remains a great need for improved methods of killing or inactivating pathogenic viruses in the respiratory tract of animals generally, and of man in particular.